Naphtho[1,8-de][1,2]Oxazin-4-ol: Precursor to 1,2,8-Trisubstituted Naphthalenes and 1-Unsubstituted Naphtho[1,2-d]isoxazole 2-Oxide: A Novel Isomerization of the N-Oxide to Nitrile Oxide en Route to Isoxazol(in)es

Naphtho[1,8-de][1,2]oxazin-4-ol and its acyl or benzyl derivatives ring open to various 2,8-dihydroxy-1-naphthonitriles, which, through (de)protection protocols and reduction, afford the target (E)-2-hydroxy-8-methoxy-1-naphthaldehyde. This was converted to its corresponding oxime, which was oxidatively o-cyclized with phenyliodine(III) diacetate (PIDA) to 9-methoxynaphtho[1,2-d]isoxazole 2-oxide. The latter, in deuterated DMSO at room temperature, was rearranged to its isomer 2-hydroxy-8-methoxy(naphthalen-1-yl)nitrile oxide. The isomerization was detected by time-course plot 1H NMR spectroscopy and further identified from its 13C NMR and HRMS spectra. The nitrile oxide was stable in (non)deuterated DMSO for at least 18 h. A 3,4-bis(2-hydroxy-8-methoxynaphthalen-1-yl)-1,2,5-oxadiazole 2-oxide, as a dimerization product or an isocyanate as a rearrangement isomer, was ruled out, the former by its HRMS spectrum and the latter by its 1,3-dipolar cycloaddition reactions to substituted isoxazoles.

was properly placed for further deprotection and reduction to the target 16.Thus, by reducing 17 with either DIBAL in dry THF at −78 °C [62] or with PtO2 in an equal volume of HCO2H/H2O at 55-60 °C [64], 12 was obtained in 36% and 45% yields, respectively.The reduction of 17 to 14 proved difficult, under either the standard DIBAL conditions [62] or an attempted modification (initiating the reaction at 0 °C and allowing a long period at room temperature), and gave a disappointing 15% yield and an overall 3% yield from 2. [a] Isolated yields after purification using flash column chromatography.
In our next attempt (Scheme 2, Route c), we anticipated that the 6-membered intramolecular H bond in aldehyde 19 between the CHO oxygen atom and the OH hydrogen atom would be strong enough to survive in DMF and would thus encourage selective methylation at the peri position.Thus, the ring-opening of 2 to 5 [10]  [a] Isolated yields after purification using flash column chromatography.
forded the targets 14 and 20 in 19% and 47% yields, respectively [15].The formation of 20 implies that in a DMF solution of 19, the intramolecular H bond between the CHO group and the peri-OH group survives, whereas that between the CHO group and the ortho OH group is disrupted by intermolecular H bonding with the solvent.The outcome of this effort was a 4% overall yield of 6, which was more or less the same as in Scheme 2, Route b.
The next plan was to alkylate 5, reduce the resultant nitrile 13 to the corresponding aldehyde 21, and then selectively demethylate to the target 14 (Scheme 2, Route d).Accordingly, the dimethylation of 5 (MeI and Na2CO3, in aqueous acetone, under mild heating) [61], gave 13 in a satisfying 78% yield.The latter was reduced to the aldehyde 21 in a moderate yield by a modification of the standard DIBAL conditions [62], as described earlier.Aldehyde 21 was then subjected to what we hoped would be the selective deprotection of the 2-OMe group to the target 14 in a useful yield.Thus, the selective demethylation of 21 to 14 entailed various reagents and conditions, as depicted in Table 2.For a detailed description of the procedures, see Materials and Methods (Section 3) [66,67].We can assume that at low temperature, the peri-OMe group in 21 is intramolecularly engaged in a H bond with the CHO group for most of the time.Consequently, this H bonding interaction allows a relatively easier demethylation of its more available o-OMe counterpart.The moderate yields of the last two steps of this reaction sequence towards 14 diminished its value, despite an increase in the overall yield to 18%. [a] Isolated yields after purification using flash column chromatography.
The final attempt to synthesize 14 is delineated in Scheme 3. Accordingly, we started with an O-benzylation of 2 and then a ring-opening of the resulting 4-(benzyloxy)naphtho[1,8-de][1,2]oxazine (by heating in DMF) to the target precursor 23.Further, we envisaged the methylation of the peri-OH group, the reduction of nitrile to aldehyde, and the debenzylation of the OBn group.For the benzylation step, we slightly modified the conditions applied by Luo and Zheng and co-workers [68] to convert 2-hydroxy-1-naphthaldehyde to 2-(benzyloxy)-1-naphthaldehyde.Starting from 2, we used benzyl bromide, instead of benzyl chloride, in the presence of K2CO3 and KI and stirred the reaction in acetone at room temperature for 18 h.Compounds 22 and 23 were identified in 12% and 61% yields, respectively.To our surprise, the intermediate 4-(benzyloxy)naphtho [ [a] Isolated yields after purification using flash column chromatography.
Thus, compound 2 was reacted with TBSCl and imidazole in dry DMF at room temperature (Scheme 2, Route a), following a relevant report by Bencivenni and co-workers [61], then heated at 120 • C for a short period of time, under the conditions used in our previous report (Scheme 1b) [10].The expected ring-opened 2-TBS protected 1-naphthonitrile 11 and the unprotected 1-naphthonitrile 5 were produced in 31% and 50% yields, respectively.Compound 5 most likely resulted from 11 by the cleavage of its TBS group.The methylation of 11 (MeI and K 2 CO 3 in dry acetone), under the conditions used by Bencivenni and coworkers [61] on 7-[(tert-butyldimethylsilyl)oxy]naphthalen-1-ol, furnished the selectively methylated nitrile 12 in a 43% yield and dimethylated nitrile 13 in an 18% yield.Nitrile 12 was then reduced to aldehyde 14 with DIBAL in toluene at 0 • C [62] and then at room temperature, in our case.The overall yield of 14 from 2, as described in Scheme 2, was only 2.8%.
In our next attempt (Scheme 2, Route b), we acetylated 2 with acetic anhydride, according to an old, published procedure [8], and obtained acetate 15 in a 70% yield.The ring-opening of 15 in DMF at 120 • C, under conditions used previously [10], afforded 1-naphthonitrile 16 in a 72% yield.We then conducted a search for methylation of the OH group of 16 without cleaving the acetyl group (Table 1).For a detailed description of the procedures, see Materials and Methods (Section 3) [63].The origin of 18 may well have been derived from an intermolecular acetylation between two molecules of 16, followed by the methylation of the resulting 8-acetoxy-1-cyanonaphthalen-2-olate.The methylation outcome of 16 remained the same, under different conditions but with varying yields of 17 and 18.It was interesting to note that the solvent effect in the last two attempts apparently favored 17 (41% yield) compared to 18 (9% yield).Moreover, the OMe group in 17 was properly placed for further deprotection and reduction to the target 16.Thus, by reducing 17 with either DIBAL in dry THF at −78 • C [62] or with PtO 2 in an equal volume of HCO 2 H/H 2 O at 55-60 • C [64], 12 was obtained in 36% and 45% yields, respectively.The reduction of 17 to 14 proved difficult, under either the standard DIBAL conditions [62] or an attempted modification (initiating the reaction at 0 • C and allowing a long period at room temperature), and gave a disappointing 15% yield and an overall 3% yield from 2.
In our next attempt (Scheme 2, Route c), we anticipated that the 6-membered intramolecular H bond in aldehyde 19 between the CHO oxygen atom and the OH hydrogen atom would be strong enough to survive in DMF and would thus encourage selective methylation at the peri position.Thus, the ring-opening of 2 to 5 [10] and the reduction of the CN group in 5 with calcium hypophosphite, in the presence of a base and nickel(II) acetate tetrahydrate, according to Estelle Métay, Marc Lemaire, and co-workers [65], who reduced 1-naphthonitrile to 1-naphthaldehyde in an 85% yield, led to a disappointing 29% yield of 19.Aryl nitriles bearing OH groups are tolerant to these conditions.The methylation of 19 (dry DMF and at room temperature, in the presence of MeI and K 2 CO 3 ) afforded the targets 14 and 20 in 19% and 47% yields, respectively [15].The formation of 20 implies that in a DMF solution of 19, the intramolecular H bond between the CHO group and the peri-OH group survives, whereas that between the CHO group and the ortho OH group is disrupted by intermolecular H bonding with the solvent.The outcome of this effort was a 4% overall yield of 6, which was more or less the same as in Scheme 2, Route b.
The next plan was to alkylate 5, reduce the resultant nitrile 13 to the corresponding aldehyde 21, and then selectively demethylate to the target 14 (Scheme 2, Route d).Accordingly, the dimethylation of 5 (MeI and Na 2 CO 3, in aqueous acetone, under mild heating) [61], gave 13 in a satisfying 78% yield.The latter was reduced to the aldehyde 21 in a moderate yield by a modification of the standard DIBAL conditions [62], as described earlier.Aldehyde 21 was then subjected to what we hoped would be the selective deprotection of the 2-OMe group to the target 14 in a useful yield.Thus, the selective demethylation of 21 to 14 entailed various reagents and conditions, as depicted in Table 2.For a detailed description of the procedures, see Materials and Methods (Section 3) [66,67].We can assume that at low temperature, the peri-OMe group in 21 is intramolecularly engaged in a H bond with the CHO group for most of the time.Consequently, this H bonding interaction allows a relatively easier demethylation of its more available o-OMe counterpart.The moderate yields of the last two steps of this reaction sequence towards 14 diminished its value, despite an increase in the overall yield to 18%.
The final attempt to synthesize 14 is delineated in Scheme 3. Accordingly, we started with an O-benzylation of 2 and then a ring-opening of the resulting 4-(benzyloxy)naphtho[1,8de][1,2]oxazine (by heating in DMF) to the target precursor 23.Further, we envisaged the methylation of the peri-OH group, the reduction of nitrile to aldehyde, and the debenzylation of the OBn group.For the benzylation step, we slightly modified the conditions applied by Luo and Zheng and co-workers [68] to convert 2-hydroxy-1-naphthaldehyde to 2-(benzyloxy)-1-naphthaldehyde.Starting from 2, we used benzyl bromide, instead of benzyl chloride, in the presence of K 2 CO 3 and KI and stirred the reaction in acetone at room temperature for 18 h.Compounds 22 and 23 were identified in 12% and 61% yields, respectively.To our surprise, the intermediate 4-(benzyloxy)naphtho[1,8-de][1,2]oxazine was not detected.Apparently, the oxazine suffered ring-opening in the presence of the base.Indeed, this result was experimentally verified by stirring 2 with K 2 CO 3 and KI in acetone, and after 4 h, 5 was obtained as a single product.It may be argued that benzylation could take place either sequentially, first on 2 and then on ring-opened 22 to 23, or on the ring-opened 5.The higher yield of 23 points to the former process.In the second step of this reaction sequence, 23 was methylated (MeI and K 2 CO 3 in dry acetone under reflux) [61] to afford the 8-OMe derivative 24 in an excellent 94% yield.The reduction of the nitrile group of 24 was accomplished under conditions described earlier [62], and aldehyde 25 was thus obtained in a moderate 55% yield.The debenzylation of 25 took place with H 2 and Pd/C as catalysts, according to an analogously reported procedure [69] that gave 14 in an excellent 92% yield.The overall yield of 14 from 2 by this route (Scheme 3) was increased to 29%.Having established a viable route to target 14, we moved to the synthesis of (E)-oxime 6 and its reaction with PIDA (Scheme 4).Compound 6 was accordingly obtained in a 78% yield by a method in a recent report by Tzeli, Tsoungas, and co-workers [60].Compound 6 was then subjected to oxidation with PIDA in non-nucleophilic dry t-BuOH at room temperature, to afford isoxazole-2-oxide 8 in a very good yield (81%).We propose that the initially formed organoiodo complex A by the ligand coupling mechanism [70]  The stability of 8 was apparently due to the intramolecular H bonding between the OMe peri substituent and the sp 2 C-1 hydrogen atom (2.006 Å) [60], which impeded the ringopening of the isoxazole ring.This result could well serve as a rationale for the nonisolable naphtho[1,2-d]isoxazole 2-oxide (4), which lacks this particular stabilizing factor (Scheme 1a) [11].When first recorded, the 1 H NMR spectrum of 8 in DMSO-d 6 did show the peaks corresponding to its structure.When recorded again the next day, its 1 H NMR spectrum was identified as that of the nitrile oxide 9 (see Supplementary Figure S59 for superimposed and Figure S60 for stacked 1 H NMR spectra of 8 and 9).This novel isomerization of 8 to 9 was also detected by 1 H NMR spectroscopy, which was measured by a time-course plot (see Supplementary Figure S61).When recorded in CDCl 3 , the 1 H and 13 C NMR spectra of 8 confirmed that the compound is stable in this solvent for at least 18 h.We stirred a sample of 8 in DMSO-d 6 and after 6 h recorded the 1 H and 13 C NMR spectra.As with the previously recorded NMR spectra of nitrile oxide 9, in the 1 H NMR spectrum in DMSO-d 6 , the OH proton at a high field was not visible, and there was a total of five aromatic protons belonging to the naphthalen-2-ol ring in the range of 7.90-7.02ppm.The characteristic singlet of the methyl group was found at 3.92 ppm.The 13  ).The confirmation of the nitrile oxide structure of 9 and not its isocyanate isomer came from 1,3-dipolar cycloaddition reactions of in situ generated nitrile oxide 9 with various dipolarophiles, which produced substituted isoxazoles 10a-d (Scheme 5).The reactions took place by dissolving isoxazole 2-oxide 8 in DMSO, under an atmosphere of nitrogen, followed by the addition of the appropriate dipolarophile (DMAD, phenylacetylene, methyl acrylate, or styrene, stirred at room temperature for 18 h).The substituted isoxazoles 10a-d were produced in 85%, 93%, 89%, and 97% yields, respectively.It was suggested that when 2-oxide 8 was dissolved in DMSO, the solvated species D could suffer disruption of the intramolecular H bond between the MeO group and the C-1 hydrogen atom, allowing for the ring-opening of the isoxazole ring to its nitrile oxide isomer 9, which then underwent 1,3-dipolar cycloaddition with the dipolarophiles (Scheme 5).

Materials and Methods
The organic solutions were concentrated by rotary evaporation at 40 • C under 15 Torr.Melting points were taken using a Büchi 510 apparatus (Büchi Labortechnik AG, Flawil, Switzerland) and are uncorrected. 1H and 13 C NMR spectra were measured in CDCl 3 or DMSO-d 6 on a 400 MHz Brüker Avance spectrometer (Brüker BioSpin GmbH, Rheinstetten, Germany). 1 H chemical shifts are reported in ppm from an internal standard TMS, residual CHCl 3 (7.26ppm), or DMSO (2.50 ppm). 13C NMR chemical shifts are reported in ppm from an internal standard TMS, residual CHCl 3 (77.00ppm), or DMSO (39.43 ppm).High resolution ESI mass spectra were measured on a Thermo Fisher Scientific Orbitrap XL system (Thermo Fisher Scientific, Waltham, MA, USA).IR spectra were acquired on an Agilent Cary 630 FTIR spectrophotometer (Agilent Technologies, 5301 Stevens Creek Blvd.CA, USA) as solids and are reported in wave numbers (cm −1 ).Analytical thin layer chromatography (TLC) was performed with TLC plates (Merck 70-230 mesh silica gel).TLC visualization took place under a 254 nm UV light source.Purification of the reaction products was generally conducted by flash column chromatography using Carlo Erba Reactifs-SDS silica gel 60.Solvents, reagents, and catalysts were used as received from the manufacturers, Thermo Scientific™ (Paisely, U.K.), Sigma-Aldrich (St. Louis, MO, USA), and Merck Chemicals GmbH (Darmstadt, Germany), except for DCM, EtOAc, and hexane, which were dried and purified according to the recommended procedures.To a solution of compound 2 (500 mg, 2.2 mmol, 1 equiv) in dry DMF (15 mL), under an atmosphere of N 2 , was added imidazole (374 mg, 5.5 mmol, 2.5 equiv) and TBSCl (398 mg, 2.64 mmol, 1.2 equiv), and the reaction was left stirring at room temperature for 2 h (TLC analysis showed the absence of the starting material spot and the presence of a new spot).The reaction mixture was then heated at 120 • C for 0.5 h.TLC examination revealed the absence of the starting material spot and the presence of two new spots.To the cooled reaction mixture, water (100 mL) was added and extracted with EtOAc (3 × 20 mL), and the combined organic extracts were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , and concentrated in a vacuum.The acquired crude residue was purified by flash column chromatography (25% EtOAc in hexane) to give the title compounds.

Synthesis of Naphtho[1,8-de][1,2]oxazin-4-yl Acetate (15)
A solution of 2 (500 mg, 2.7 mmol, 1 equiv) in freshly distilled acetic anhydride (10 mL, 41 equiv), under an atmosphere of N 2 , was stirred at room temperature for 18 h (TLC showed the absence of a starting material spot and the presence of one new spot).Ice water (30 mL) was added, and the reaction mixture was stirred for 0.5 h at room temperature.The reaction mixture was then extracted with EtOAc (3 × 15 mL), and the combined organic extracts were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , and concentrated under vacuum.The acquired crude residue was purified by flash column chromatography (17% EtOAc in hexane) to give the title compound (429 mg, 70%) as a brown oil; R f = 0.05 (20% EtOAc in hexane); 1

Synthesis of 1-Cyano-8-hydroxynaphthalen-2-yl Acetate (16)
A solution of 15 (400 mg, 2.16 mmol) in DMF (8 mL) was heated at 120 • C for 45 min.(TLC analysis showed the absence of a starting material spot and the presence of a new spot).Water (30 mL) was added, and the reaction mixture was extracted with Et 2 O (3 × 15 mL).The combined organic extracts were dried (Na 2 SO 4 ), and the solvent was removed under vacuum.The residue was purified by flash column chromatography (50% EtOAc in hexane) to give the title compound (267 mg, 72%) as a brown solid; m.p. = 165-167 • C; R f = 0.13 (20% ethyl acetate in hexane); 1  To a solution of 16 (50 mg, 0.22 mmol, 1 equiv) in dry acetone (5 mL), under an atmosphere of N 2 , was added oven-dried K 2 CO 3 (34 mg, 0.24 mmol, 1.1 equiv) and dimethyl sulfate (31 mg, 0.24 mmol, 1.1 equiv), and the reaction was left stirring for 24 h at room temperature.(TLC showed complete conversion of the starting material and the presence of two new spots (visualized under a UV lamp).Water (20 mL) was added; the reaction mixture was extracted with EtOAc (3 × 10 mL); and the combined organic extracts were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , and concentrated in vacuo.The acquired crude residue was purified by flash column chromatography (20% EtOAc in hexane) to give the title compounds.

Procedure B for the Synthesis of Compounds 17 and 18
To a solution of 8 (50 mg, 0.22 mmol, 1 equiv) in dry THF (5 mL), under an atmosphere of nitrogen, was added oven-dried K 2 CO 3 (34 mg, 0.24 mmol, 1.1 equiv) and MeI (34 mg, 0.24 mmol, 1.1 equiv), and the reaction mixture was left stirring for 18 h at room temperature (TLC showed complete conversion of the starting material and the presence of two new spots).Water (20 mL) was added, and the reaction mixture was extracted with EtOAc (3 × 10 mL); the combined organic extracts were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure.The acquired crude residue was purified by flash column chromatography (20% EtOAc in hexane) to give the title compounds.

Procedure C for the Synthesis of Compounds 17 and 18
To a solution of 16 (50 mg, 0.22 mmol, 1 equiv) in dry THF (5 mL), under an atmosphere of N 2 , was added NaH (5.8 mg, 0.24 mmol, 1.1 equiv) and MeI (34 mg, 0.24 mmol, 1.1 equiv), and the reaction mixture was left stirring for 18 h at room temperature (TLC analysis showed the absence of starting material and the presence of two new spots).Water (20 mL) was added to the reaction mixture and then extracted with EtOAc (3 × 10 mL).The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , and removed under reduced pressure.The acquired crude residue was purified by flash column chromatography (20% EtOAc in hexane) to give the title compounds.

Procedure D for the Synthesis of Compounds 17 and 18
To a solution of 16 (50 mg, 0.22 mmol, 1 equiv) in dry THF (50 mL), under an atmosphere of N 2 , was added NaH (5.8 mg, 0.24 mmol, 1.1 equiv) and MeI (34 mg, 0.24 mmol, 1.1 equiv), and the reaction was left stirring for 18 h at room temperature (TLC analysis showed the absence of the starting material spot and the presence of two new spots).Water (20 mL) was added to the reaction mixture and extracted with EtOAc (3 × 10 mL); the combined organic extracts were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , and evaporated under vacuum.The acquired crude residue was purified by flash column chromatography (20% EtOAc in hexane) to give the title compounds.

Attempted Reduction of 1-Cyano-8-methoxynaphthalen-2-yl Acetate (17) with DIBAL
To a solution of 17 (50 mg, 0.27 mmol, 1 equiv) in dry THF, under an atmosphere of N 2 that was cooled to −78 • C, DIBAL (0.86 mL of 1.2 M in toluene, 0.864 mmol, 3.2 equiv) was added dropwise, and the reaction mixture was left stirring at that temperature for 0.5 h and then for 1 h at room temperature (TLC analysis showed the absence of the starting material spot and the presence of one new spot).A saturated aq.solution of NH 4 Cl (5 mL) was added dropwise, followed by 1 N HCl aq.(25 mL) and EtOAc (25 mL), and the reaction mixture was left stirring for 1 h.The organic phase was separated, and the aqueous phase was extracted with EtOAc (3 × 10 mL); the combined organic phases were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , and evaporated under vacuum.The acquired crude residue was purified by flash column chromatography (20% EtOAc in hexane) to give 2-hydroxy-8-methoxy-1-naphthonitrile (12) (23 mg, 36%) as a yellow solid, m.p. = 172-174 • C; R f = 0.09 (20% EtOAc in hexane); (the 1 H NMR data were in agreement with those reported for this compound synthesized from compound 2 (Scheme 2)).

Synthesis of 2-Hydroxy-8-methoxy-1-naphthaldehyde (14)
To a solution of 17 (250 mg, 1 mmol, 1 equiv) in dry toluene (10 mL) at 0 • C, under an atmosphere of N 2 , was added DIBAL (1.67 mL of 1.2 M in toluene, 2 mmol, 2 equiv), and the reaction mixture was stirred for 0.5 h and then left stirring for 18 h at room temperature.Upon completion of the reaction (TLC examination), the solvent was removed under vacuum, and water (20 mL) was carefully added to the residue.The resulting mixture was cooled to 0 • C, followed by the dropwise addition of 1 M HCl aq. until pH = 1.The aqueous solution was extracted with EtOAc (3 × 10 mL), and the combined organic extracts were washed with brine (20 mL) and dried over anhydrous Na 2 SO 4 ; the solvent was removed under vacuum.The acquired crude residue was purified by flash column chromatography (17% EtOAc in hexane) to give the title compound (31.5 mg, 15%) as a yellow solid, m.p. = 67-69 • C (lit.[60], m.p. = 68-70 • C); R f = 0.54 (20% ethyl acetate in hexane); (the 1 H NMR data were in agreement with those reported for this compound synthesized from 12 (Scheme 2) and with those previously reported) [60].

Synthesis of 2,8-Dimethoxy-1-naphthonitrile (13)
To a stirred solution of 5 (300 mg, 1.62 mmol, 1 equiv) in acetone (10 mL) was added MeI (460 mg, 3.28 mmol, 2.02 equiv), followed by Na 2 CO 3 (175 mg, 1.65 mmol, 1.02 equiv) and H 2 O (2 mL).The reaction mixture was gently heated for 3 h, during which time TLC analysis showed complete conversion of the starting material and the presence of one new spot.The solvents were removed under reduced pressure and the oily residue was triturated with hexane to give the title compound (270 mg, 78%) as a colorless solid (hexane), m.p. = 147-149 • C; R f = 0.21 (20% ethyl acetate in hexane); (the 1 H NMR data were in agreement with those reported for this compound synthesized from compound 2 (Scheme 2)).
3.20.Procedure H for the Synthesis of 2-Hydroxy-8-methoxy-1-naphthaldehyde ( 14), 8-Hydroxy-2-methoxy-1-naphthaldehyde (20), and 2,8-Dihydroxy-1-naphthaldehyde (19) A solution of 21 (50 mg, 0.231 mmol, 1 equiv) in dry DCM (10 mL), over an atmosphere of N 2 , was cooled to 0 • C; then, BBr 3 (230 µL of a 1M solution in DCM, 0.231 mmol, 1 equiv) was added dropwise, and the reaction was left stirring at room temperature for 1 h.TLC analysis showed complete conversion of the starting material and the presence of three new spots (visualized under a UV lamp).The reaction mixture was cooled to 0 • C, quenched slowly with cold water (30 mL), and extracted with DCM (3 × 20 mL); the combined organic extracts were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , and concentrated under vacuum.The acquired crude residue was purified by flash column chromatography (11% EtOAc in hexane) to give the title compounds.; (the 1 H NMR data were in agreement with those reported for this compound synthesized from (12) (Scheme 2) and with those previously reported) [60].Compound 20: (5 mg, 11%) as a yellow solid, m.p. = 110-112 • C; R f = 0.28 (20% ethyl acetate in hexane); (the 1 H NMR data were in agreement with those reported for this compound synthesized from compound (21) (Scheme 2) and with those previously reported) [15].Compound 19: (14.3 mg, 33%) as a yellow solid, m.p. = 194-196 • C (lit.[14], m.p. = 195-197 • C); R f = 0.51 (33% EtOAc in hexane); (the 1 H NMR data were in agreement with those reported for this compound synthesized from compound (13) (Scheme 2) and with those previously reported) [14].A solution of 21 (50 mg, 0.231 mmol, 1 equiv) in dry DCM (10 mL), over an atmosphere of N 2 , was cooled to −15 • C; then, BBr 3 (230 µL of a 1 M solution in DCM, 0.231 mmol, 1 equiv) was added dropwise over a period of 10 min.The reaction was allowed to slowly reach room temperature and was left stirring for 1 h, after which TLC analysis showed complete conversion of the starting material and the presence of three new spots (visualized under a UV lamp).The reaction mixture was cooled to 0 • C, quenched slowly with cold water (30 mL), and extracted with DCM (3 × 20 mL).The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure.The acquired crude residue was purified by flash column chromatography (11% EtOAc in hexane) to give the title compounds.
Compound 14: (25.9 mg, 56%) as a yellow solid, m.p. = 67-68  To a stirred solution of 2 (500 mg, 2.7 mmol, 1 equiv) in dry acetone (20 mL), under an atmosphere of N 2 , was added benzyl bromide (462 mg, 2.7 mmol, 1 equiv), ovendried K 2 CO 3 (391 mg, 2.83 mmol, 1.05 equiv), and KI (89 mg, 0.54 mmol, 0.2 equiv).The reaction was left stirring at room temperature for 18 h, after which TLC analysis indicated the absence of the starting material and the presence of two new spots.The solvent was removed under vacuum, the residue was dissolved in EtOAc (30 mL) and washed with water (3 × 10 mL).The organic extract was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.The acquired crude residue was purified by flash column chromatography (20% EtOAc in hexane) to give the title compounds 22 and 23.

Synthesis of 2-Hydroxy-8-methoxy-1-naphthaldehyde (14)
To a stirred solution of 25 (20 mg, 0.099 mmol) in anhydrous MeOH (5 mL), under an atmosphere of N 2 , 5% Pd/C (1 mg, 5%) was added, and the reaction was purged with H 2 .Stirring at room temperature was continued for 18 h (TLC analysis showed complete conversion of the starting material and the presence of a new spot.The reaction mixture was filtered, and the solvent was removed under vacuum.To the remaining residue, EtOAc (20 mL) was added and then washed with brine (10 mL).The organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.The acquired crude product was purified by flash column chromatography (20% EtOAc in hexane) to give the title compound (18 mg, 92%) as a yellow solid, m.p. = 67-69 • C (lit.[60], m.p. = 68-70 • C); R f = 0.54 (20% ethyl acetate in hexane); (the 1 H NMR data were in agreement with those reported for this compound synthesized from compound 12 (Scheme 2) and with those previously reported) [60].

Synthesis of 9-Methoxynaphtho[1,2-d]isoxazole 2-Oxide (8)
To a stirred solution of (E)-oxime 6 (150 mg, 0.70 mmol, 1 equiv) in dry t-BuOH (15 mL), under an atmosphere of N 2 , PIDA (450 mg, 1.40 mmol, 2 equiv) was added, and the resulting mixture was stirred at room temperature for 0.5 h.TLC analysis showed the absence of the starting material and the presence of a new spot.Water (15 mL) was added, followed by the dropwise addition of 5% NaHCO 3 aq.solution until pH = 7-8.The solvents were evaporated under vacuum and water (20 mL) was added to the residue, and the resulting mixture was extracted with EtOAc (3 × 10 mL).The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure.The acquired residue was purified by flash column chromatography (17% EtOAc in hexane) to give the title compound (120 mg, 81%) as a yellow solid, m.p. = 91-93 • C; R f = 0.44 (20% EtOAc in hexane); 1 H NMR (400 MHz, CDCl 3 ) δ: 8.10 (s, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 4.07 (s, 3H); 13  A solution of isoxazole 2-oxide 8 (5 mg, 0.023 mmol) in dry DMSO-d 6 (0.5 mL), under an atmosphere of N 2 , was stirred at room temperature for 6 h.TLC analysis revealed the absence of the starting material and the presence of a new spot.The solution was transferred to an NMR tube and the 1 H and 13 C NMR spectra of the new compound were recorded.R f = 0.2 (20% EtOAc in hexane); 1   A solution of 2-oxide 8 (5 mg, 0.023 mmol, 1 equiv) in dry DMSO (1.5 mL), under an atmosphere of N 2 , was stirred at room temperature for 15 min.DMAD, phenylacetylene, methyl acrylate, or styrene (0.069 mmol, 3 equiv) was added, and the resulting mixture was stirred at room temperature for 18 h.TLC analysis showed the absence of the starting material and the presence of a new spot (visualized under a UV lamp).The reaction was quenched with water (15 mL), and the resulting mixture was extracted with EtOAc (3 × 10 mL).The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , and concentrated under vacuum.The acquired residue was purified by flash column chromatography (17% EtOAc in hexane) to give the title compounds.
collapses to o-naphthoquinone nitrosomethide intermediate B; the driving force is the rupture of the weaker O-I bond compared to the N-O bond.B underwent a 6π-electrocyclization to the non-aromatic naphthoisoxazole-2-oxide C, which aromatized to stable 2-oxide 8.
C NMR spectrum in DMSO-d 6 showed 11 signals.According to Koyama, Takata, and co-workers, [71] quaternary signals of nitrile groups usually turn up under the residual DMSO signal so that for nitrile oxide 9 the total number of carbon atoms was 12, as expected.High-resolution mass spectrometry (HRMS) analysis confirmed the expected molecular ion at m/z = 216.0661[M + H] + (ESI), which took up a proton and was calculated for C 12 H 10 NO 3 m/z = 216.0661.There was no peak at m/z = 431.1243[M + H] + corresponding to the dimerization of 9 to its 1,2,5oxadiazole 2-oxide (Scheme 5
and the reduction of